Bcl-2/Bax protein ratio predicts 5-fluorouracil sensitivity independently of p53 status
| Autor: | C Didelot, Jean-Louis Merlin, J. F. Mirjolet, Muriel Barberi-Heyob, Joseph Abecassis, J P Peyrat, Régine Millon |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2000 |
| Předmět: |
mdm2
Cancer Research Cell cycle checkpoint Apoptosis Breast Neoplasms Adenocarcinoma Gene product Bcl-2-associated X protein Proto-Oncogene Proteins Translational regulation Tumor Cells Cultured Humans RNA Messenger bcl-2-Associated X Protein Regulation of gene expression biology G1/S arrest Bcl-2/Bax ratio Dose-Response Relationship Drug Carcinoma Cell Cycle Regular Article Cell cycle Genes p53 Molecular biology Up-Regulation Gene Expression Regulation Neoplastic Pancreatic Neoplasms Oncology Proto-Oncogene Proteins c-bcl-2 Cell culture p53 status Head and Neck Neoplasms 5-FU sensitivity biology.protein Female Fluorouracil |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | p53 tumour-suppressor gene is involved in cell growth control, arrest and apoptosis. Nevertheless cell cycle arrest and apoptosis induction can be observed in p53-defective cells after exposure to DNA-damaging agents such as 5-fluorouracil (5-FU) suggesting the importance of alternative pathways via p53-independent mechanisms. In order to establish relationship between p53 status, cell cycle arrest, Bcl-2/Bax regulation and 5-FU sensitivity, we examined p53 mRNA and protein expression and p53 protein functionality in wild-type (wt) and mutant (mt) p53 cell lines. p53 mRNA and p53 protein expression were determined before and after exposure to equitoxic 5-FU concentration in six human carcinoma cell lines differing in p53 status and displaying marked differences in 5-FU sensitivity, with IC 50 values ranging from 0.2–22.6 mM. 5-FU induced a rise in p53 mRNA expression in mt p53 cell lines and in human papilloma virus positive wt p53 cell line, whereas significant decrease in p53 mRNA expression was found in wt p53 cell line. Whatever p53 status, 5-FU altered p53 transcriptional and translational regulation leading to up-regulation of p53 protein. In relation with p53 functionality, but independently of p53 mutational status, after exposure to 5-FU equitoxic concentration, all cell lines were able to arrest in G1. No relationship was evidenced between G1 accumulation ability and 5-FU sensitivity. Moreover, after 5-FU exposure, Bax and Bcl-2 proteins regulation was under p53 protein control and a statistically significant relationship (r= 0.880,P= 0.0097) was observed between Bcl-2/Bax ratio and 5-FU sensitivity. In conclusion, whatever p53 status, Bcl-2 or Bax induction and Bcl-2/Bax protein ratio were correlated to 5-FU sensitivity. © 2000 Cancer Research Campaign |
| Databáze: | OpenAIRE |
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